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ACS Surgery: Principles and Practice
1 BASIC SURGICAL AND PERIOPERATIVE CONSIDERATIONS
5 POSTOPERATIVE PAIN
Henrik Kehlet, M.D., Ph.D., F.A.C.S. (Hon.)
Approach to the Patient with Postoperative Pain
Pain may usefully be classified into two varieties: acute and chron-
ic. As a rule, postoperative pain is considered a form of acute pain,
though it may become chronic if it is not effectively treated.
Postoperative pain consists of a constellation of unpleasant sen-
sory, emotional, and mental experiences associated with auto-
nomic, psychological, and behavioral responses precipitated by the
surgical injury. Despite the considerable progress that has been
made in medicine during the past few decades, the apparently
simple problem of how to provide total or near total relief of post-
operative pain remains largely unsolved. Pain management does
not occupy an important place in academic surgery. However,
government agencies have attempted to foster improved postoper-
ative pain relief, and guidelines have been published.1-3 In 2001,
the Joint Commission on Accreditation of Healthcare Organiza-
tions (JCAHO) introduced standards for pain management,4 stat-
ing that patients have the right to appropriate evaluation and man-
agement and that pain must be assessed.
Postoperative pain relief has two practical aims.The first is pro-
vision of subjective comfort, which is desirable for humanitarian
reasons. The second is inhibition of trauma-induced nociceptive
impulses to blunt autonomic and somatic reflex responses to pain
and to enhance subsequent restoration of function by allowing the
patient to breathe, cough, and move more easily. Because these
effects reduce pulmonary, cardiovascular, thromboembolic, and
other complications, they may lead secondarily to improved post-
operative outcome.
Inadequate Treatment of Pain
A common misconception is that pain, no matter how severe,
can always be effectively relieved by opioid analgesics. It has
repeatedly been demonstrated, however, that in a high proportion
of postoperative patients, pain is inadequately treated.5,6 This dis-
crepancy between what is possible and what is practiced can be
Table 1—Contributing Causes of
Inadequate Pain Treatment
Insufficient knowledge of drug pharmacology
among surgeons and nurses
Uniform (p.r.n.) prescriptions
Lack of concern for optimal pain relief
Failure to give prescribed analgesics
Fear of side effects
Fear of addiction
5 POSTOPERATIVE PAIN — 1
attributed to a variety of causes [see Table 1], which to some extent
can be ameliorated by increased teaching efforts. In general, how-
ever, the scientific approach to postoperative pain relief has not
been a great help to surgical patients in the general ward, where
intensive surveillance facilities may not be available.
Guidelines for
Postoperative Pain
Treatment
The recommendations
provided below are aimed at
surgeons working on the gen-
eral surgical ward; superior
regimens have been constructed by specialized groups interested
in postoperative pain research, but these regimens are not cur-
rently applicable to the general surgical population, unless an
acute pain service is available. Consideration is given to the effi-
ciency of each analgesic technique, its safety versus its side effects,
and the cost-efficiency problems arising from the need for inten-
sive surveillance. For several analgesic techniques, evidence-based
recommendations are now available.7 For many others, however,
there are not sufficient data in the literature to form a valid scien-
tific database; accordingly, recommendations regarding their use
are made on empirical grounds only.
In the past few years, efforts have been made to develop proce-
dure-specific perioperative pain management guidelines. The
impetus for these efforts has been the realization that the analgesic
efficacy may be procedure dependent and that the choice of anal-
gesia in a given case must also depend on the benefit-to-risk ratio,
which varies among procedures. In addition, it is clear that some
analgesic techniques will only be considered for certain specific
operations (e.g., peripheral nerve blocks, cryoanalgesia, and
intraperitoneal local anesthesia).8-10 At present, these procedure-
specific guidelines are still largely in a developmental state and are
available only for laparoscopic cholecystectomy, colon surgery,
hysterectomy, and hip replacement.10-12
THORACIC PROCEDURES
Pain after thoracotomy is
severe, and pain therapy
should therefore include a
combination regimen, pre-
ferably comprising epidur-
al local anesthetics and
opioids plus systemic non-
steroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase-
2 (COX-2) inhibitors (depending on risk factors). If the epidural
regimen is not available, NSAIDs and systemic opioids should be
© 2005 WebMD, Inc. All rights reserved.
1 BASIC SURGICAL AND PERIOPERATIVE CONSIDERATIONS
Thoracic
Cardiac Noncardiac
Give systemic opioids with Give epidural local
NSAIDs. anesthetic–opioid combination
with systemic NSAIDs or
Consider epidural
COX-2 inhibitors.
local anesthetic–opioid
If this combination is not
combination
available, give systemic
opioids with NSAIDs or
COX-2 inhibitors.
Consider cryoanalgesia.
ACS Surgery: Principles and Practice
5 POSTOPERATIVE PAIN — 2
Combine psychological preparation with
pharmacologic and other interventions to treat
postoperative pain
Consider recommended combination regimes.
Acetaminophen is recommended as a basic component
of multimodal analgesia in any of the settings below.
Abdominal
Major Minor (laparoscopic) Pelvic
Give epidural local Give incisional/
anesthetic–opioid intraperitoneal local
combination (add NSAIDs anesthetic with
or COX-2 inhibitors if
systemic NSAIDs or
analgesia is insufficient).
COX-2 inhibitors.
If this combination is not
available, give systemic
opioids with NSAIDs or
COX-2 inhibitors.
Gynecologic
Give systemic opioids with
NSAIDs or COX-2 inhibitors.
Consider epidural local
anesthetic–opioid
combination in high-risk
patients.
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1 BASIC SURGICAL AND PERIOPERATIVE CONSIDERATIONS 5 POSTOPERATIVE PAIN — 3

Approach to the Patient with Postoperative Pain

Peripheral

Vascular Superficial Major joint procedures

Give epidural local anesthetics Give incisional local anesthetic Give intrathecal local anesthetic
with systemic NSAIDs and systemic opioids with plus morphine and systemic
or NSAIDs or COX-2 inhibitors. NSAIDs or COX-2 inhibitors
Give systemic opioids with Consider peripheral nerve or
NSAIDs. blockade.
Give a peripheral nerve block
(single dose or continuous)
with systemic NSAIDs or
COX-2 inhibitors.
Consider continuous epidural
local anesthetic–opioid
combination in high-risk patients
Prostatectomy with systemic NSAIDs.

Open: Give epidural local

anesthetic–opioid
combination with systemic
NSAIDs or COX-2 inhibitors.
Transurethral resection:
Give systemic opioids with
NSAIDs or COX-2 inhibitors.

Final choice of treatment

Make final choice of treatment modality

on the basis of
• Efficiency of analgesic techniques
• Side effects and additive effects
• Availability of surveillance, if required
© 2005 WebMD, Inc. All rights reserved.
1 BASIC SURGICAL AND PERIOPERATIVE CONSIDERATIONS
given to obtain the documented synergistic-additive effect. Cryo-
analgesia is useful because it is moderately effective, easy to per-
form, free of significant side effects, and relatively inexpensive.
Paravertebral blocks are also effective but necessitate continuous
infusion. Acetaminophen is recommended as a basic analgesic
for multimodal analgesia.
Pain after cardiac operation with sternotomy is less severe, and
systemic opioids plus NSAIDs are recommended. The combined
regimen of epidural local anesthetics and opioids is recommended
when more effective pain relief is necessary, and it may reduce car-
diopulmonary morbidity.13
ABDOMINAL
PROCEDURES
Pain after major and up-
per abdominal operations is
severe, and a combined reg-
imen of epidural local anes-
thetics and opioids is rec-
ommended because it has
proved to be very effective and to have few and acceptable side ef-
fects.11,12,14 Furthermore, the epidural regimen will reduce postop-
erative pulmonary complications and ileus, as compared with treat-
ment with systemic opioids. Systemic NSAIDs or COX-2 inhibitors
are added when needed. Acetaminophen is recommended as a
basic analgesic for multimodal analgesia.
After gynecologic operations,12 systemic opioids plus NSAIDs or
COX-2 inhibitors are recommended except in patients in whom
more effective pain relief is desirable. In such patients, the combined
regimen of epidural local anesthetics and opioids is preferable. Acet-
aminophen is recommended as a basic analgesic for multimodal
analgesia.
Pain following prostatectomy is usually not severe and may be
treated with systemic opioids combined with NSAIDs or COX-2
inhibitors and acetaminophen. However, blood loss and throm-
boembolic complications are reduced when epidural local anesthet-
ics are administered.This method is therefore recommended intra-
operatively and continued in selected high-risk patients for pain
relief after open prostatectomy and transurethral resection. In low-
risk patients, systemic opioids with NSAIDs or COX-2 inhibitors
and acetaminophen alleviate postoperative pain.
PERIPHERAL
PROCEDURES
After vascular proce-
dures, postoperative pain
control is probably best
achieved with epidural
local anesthetic–opioid mix-
tures, combined with sys-
temic NSAIDs or COX-2 inhibitors. Acetaminophen is recom-
mended as a basic analgesic for multimodal analgesia. This regi-
men will be effective, and the increase in peripheral blood flow
that is documented to occur with epidural local anesthetics may
lower the risk of graft thrombosis.
Pain relief after major joint procedures (e.g., hip and knee
operations)12 may involve an epidural regimen in high-risk
patients because such regimens have been shown to reduce
thromboembolic complications and intraoperative blood loss and
to facilitate rehabilitation. The severe pain noted after knee
replacement is probably best treated with epidural local anes-
thetics combined with opioids. Otherwise, for routine manage-
ment, a single intrathecal dose of a local anesthetic–low-dose
ACS Surgery: Principles and Practice
5 POSTOPERATIVE PAIN — 4
morphine combination will provide effective analgesia for the
first 8 to 16 hours, after which NSAIDs or COX-2 inhibitors may
be added. The use of peripheral nerve blocks is gaining more
popularity and may be continued postoperatively.15,16 Acetamin-
ophen is provided as a basic analgesic for multimodal analgesia.
After arthroscopic joint procedures, instillation of a local anes-
thetic and an opioid analgesic (e.g., morphine) provides effective
early postoperative pain relief.
During superficial procedures, systemic opioids combined with
NSAIDs or COX-2 inhibitors should suffice. Acetaminophen is
provided as a basic analgesic for multimodal analgesia.
Treatment Modalities
PSYCHOLOGICAL
INTERVENTIONS
Individuals differ consid-
erably in how they respond
to noxious stimuli; much of
this variance is accounted
for by psychological factors. Cognitive, behavioral, or social inter-
ventions should be used in combination with pharmacologic ther-
apies to prevent or control acute pain, with the goal of such inter-
ventions being to guide the patient toward partial or complete self-
control of pain.17,18 Sophisticated psychological techniques, such
as biofeedback and hypnosis therapy, are not applicable to a busy
surgical unit, but simple psychological techniques are a valuable
part of good medical practice.
Psychological preparation in patients with postoperative pain
has been demonstrated to shorten hospital stay and reduce post-
operative narcotic use [see Table 2].19 Psychological techniques
should be combined with pharmacologic or other interventions,
but care must be taken to ensure that the pharmacologic treat-
ment does not compromise the mental function necessary for the
success of the planned psychological intervention.
SYSTEMIC OPIOIDS
The terminology associated with the pharmacology of the opi-
oids is confusing, to say the least. Opiate is an appropriate term
for any alkaloid derived from the juice of the plant (i.e., from
opium). The proper term for the class of agents, whether exoge-
nous, endogenous, natural, or synthetic, is opioid.
Table 2—Psychological Preparation
of Surgical Patients
Procedural information—Give a careful and relevant description
of what will take place
Sensory information—Describe the sensations that will be experienced
either during or after the operation
Pain treatment information—Outline the plan for administering
sedative and analgesic medication, and encourage patients to
communicate concerns and discomforts
Instructional information—Teach patients postoperative exercises,
such as leg exercises, and show them how to turn in bed or move so
that pain is minimal
Reassurance—Reassure those who are mentally, emotionally, or
physically unable to cooperate that they are not expected to take an
active role in coping with pain and will still receive sufficient analgesic
treatment
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1 BASIC SURGICAL AND PERIOPERATIVE CONSIDERATIONS
Table 3—Opioid Receptor Types and Physiologic Actions
Prototypical Ligand
Receptor Type
Endogenous
Mu1 β-Endorphin
Mu2 β-Endorphin
Delta Enkephalin
Kappa Dynorphin
Epsilon β-Endorphin
Sigma — N-Allylnormetazocine
Mechanisms of Action
Opioids produce analgesia and other physiologic effects by
binding to specific receptors in the peripheral and central nervous
system [see Table 3]. These receptors normally bind a number of
endogenous substances called opioid peptides. These receptor-
binding interactions mediate a wide array of physiologic effects.20
Five types of opioid receptors and their subtypes have been dis-
covered: mu, delta, kappa, epsilon, and sigma receptors. Most
commonly used opioids bind to mu receptors. The mu1 receptor
is responsible for the production of opioid-induced analgesia,
whereas the mu2 receptor appears to be related to the respiratory
depression, cardiovascular effects, and inhibition of GI motility
commonly seen with opioids. In studies from 2001 and 2004,
investigators were able to obtain a reduction in the GI side effects
of morphine with a specific peripherally acting mu antagonist
without interfering with analgesia.21,22
The demonstration of the existence of peripheral opioid recep-
tors has given rise to studies investigating the effect of administer-
ing small opioid doses at the surgical site. Unfortunately, incision-
al opioid administration has no significant beneficial effect23; how-
ever, intra-articular administration does yield a modest benefit.24
The relation between receptor binding and the intensity of the
resultant physiologic effect is known as the intrinsic activity of an
opioid. Most of the commonly used opioid analgesics are agonists.
An agonist produces a maximal biologic response by binding to its
receptor. Other opioids, such as naloxone, are termed antagonists
because they compete with agonists for opioid receptor binding
sites. Still other opioids are partial agonists because they produce
a submaximal response after binding to the receptor. (An excellent
example of a submaximal response produced by partial agonists is
buprenorphine’s action at the mu receptor.)
Drugs such as nalbuphine, butorphanol, and pentazocine are
known as agonist-antagonists or mixed agonist-antagonists.20
These opioids simultaneously act at different receptor sites: their
action is agonistic at one receptor and antagonistic at another [see
Table 4]. The agonist-antagonists have certain pharmacologic
properties that are distinct from those of the more common mu
agonists: (1) they exhibit a ceiling effect and cause only submaxi-
mal analgesia as compared with mu agonists, and (2) administra-
tion of an agonist-antagonist with a complete agonist may cause a
reduction in the effect of the complete agonist.20
Agents
Morphine Morphine is the opioid with which the most clin-
ical experience has been gained. Sufficient pharmacokinetic and
ACS Surgery: Principles and Practice
5 POSTOPERATIVE PAIN — 5
Physiologic Actions
Exogenous
Morphine Supraspinal analgesia
Morphine Respiratory depression
— Spinal analgesia
Ketocyclazocine Spinal analgesia, sedation, ?visceral
analgesia
— ?Hormone
Psychotomimetic effect, dysphoria
pharmacodynamic data are available. Use of this agent is recom-
mended; it may be given orally, intravenously, or intramuscularly
[see Table 5].
Meperidine Detailed and sufficient pharmacokinetic and
pharmacodynamic data on meperidine are available. It is less suit-
able than morphine as an analgesic because its active metabolite,
normeperidine, can accumulate, even in patients with normal
renal clearance, and this accumulation can result in CNS excita-
tion and seizures.20 Other agents should be used before meperi-
dine is considered. Like morphine, meperidine can be given oral-
ly, intravenously, or intramuscularly.
Side Effects
By depressing or stimulating the CNS, opioids cause a number
of physiologic effects in addition to analgesia.The depressant effects
of opioids include analgesia, sedation, and altered respiration and
mood; the excitatory effects include nausea, vomiting, and miosis.
All mu agonists produce a dose-dependent decrease in the
responsiveness of brain-stem respiratory centers to increased car-
bon dioxide tension (PCO2).This change is clinically manifested as
an increase in resting PCO2 and a shift in the CO2 response curve.
Agonist-antagonist opioids have a limited effect on the brain stem
and appear to elicit a ceiling effect on increases in PCO2.
Opioids also have effects on the GI tract. Nausea and vomiting
are caused by stimulation of the chemoreceptor trigger zone of the
medulla. Opioids enhance sphincteric tone and reduce peristaltic
contraction. Delayed gastric emptying is caused by decreased
motility, increased antral tone, and increased tone in the first part
of the duodenum. Delay in passage of intestinal contents because
of decreased peristalsis and increased sphincteric tone leads to
greater absorption of water, increased viscosity, and desiccation of
bowel contents, which cause constipation and contribute to post-
operative ileus. Opioids also increase biliary tract pressure. Finally,
opioids may inhibit urinary bladder function, thereby increasing
the risk of urinary retention.
Several long-acting, slow-release oral opioids are currently avail-
able, but their role (in particular, their safety) in the setting of
moderate to severe postoperative pain remains to be established.
In addition, modern principles of treatment increasingly empha-
size the use of opioid-sparing analgesic approaches to enhance
recovery (see below).
EPIDURAL AND SUBARACHNOID OPIOIDS
Opioids were first used in the epidural and subarachnoid space
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1 BASIC SURGICAL AND PERIOPERATIVE CONSIDERATIONS 5 POSTOPERATIVE PAIN — 6

Table 4—Intrinsic Activity of Opioids

Receptor Type
Opioid
Mu Kappa Delta Sigma

Agonists
Morphine Agonist — — —
Meperidine (Demerol) Agonist — — —
Hydromorphone (Dilaudid) Agonist — — —
Oxymorphone (Numorphan) Agonist — — —
Levorphanol (Levo-Dromoran) Agonist — — —
Fentanyl (Duragesic) Agonist — — —
Sufentanil (Sufenta) Agonist — — —
Alfentanil (Alfenta) Agonist — — —
Methadone (Dolophine) Agonist — — —

Agonist-Antagonists
Buprenorphine (Buprenex) Partial agonist — — —
Butorphanol (Stadol) Antagonist Agonist Agonist —
Nalbuphine (Nubain) Antagonist Partial agonist Agonist —
Pentazocine (Talwin) Antagonist Agonist Agonist —
Dezocine (Dalgan) Partial agonist — — Agonist

Antagonists
Naloxone (Narcan) Antagonist Antagonist Antagonist Antagonist

in 1979. Since that time, they have become the mainstay of post-
operative management for severe pain. Epidural opioids may be
administered in a single bolus or via continuous infusions. They
are usually combined with local anesthetics in a continuous
epidural infusion to enhance analgesia.14
Mechanisms of Action
Opioids injected into the epidural or subarachnoid space cause
segmental (i.e., selective, spinally mediated) analgesia by binding
to opioid receptors in the dorsal horn of the spinal cord.25 The
lipid solubility of an opioid, described by its partition coefficient,
predicts its behavior when introduced into the epidural or sub-
arachnoid space. Opioids with low lipid solubility (i.e., hydrophilic
opioids) have a slow onset of action and a long duration of action.
Opioids with high lipid solubility (i.e., lipophilic opioids) have a
quick onset of action but a short duration of action.Thus, the lipid
solubility of an opioid determines its access to the dorsal horn via
(1) diffusion through the arachnoid granulations and (2) diffusion
into spinal radicular artery blood flow.
Subarachnoid opioids should be used when the required dura-
tion of analgesia after surgery is relatively short. When protracted
analgesia is required, epidural administration is preferred; repeat-
ed injections may be given through epidural catheters, or contin-
uous infusions may be used. Smaller doses of subarachnoid opi-
oids are generally required to produce analgesia. Ordinarily, no
more than 0.1 to 0.25 mg of morphine should be used. These
doses, which are about 10% to 20% of the size of comparably
effective epidural doses, provide reliable pain relief with few side
effects.26 Fentanyl has also been extensively used in the subarach-
noid space in a dose range of 6.25 to 50 µg. Pain relief after
administration of subarachnoid fentanyl is as potent but not as
prolonged as analgesia after administration of morphine.

Table 5—Suggested Regimens for

Systemic Morphine Administration

Intermittent Administration (Suggested Initial Dose)*

p.o. I.M. I.V. Duration (hr)

Morphine 30–50 mg 10 mg 5–10 mg 3–4

Continuous I.V. Infusion†

Morphine ≈ 3 mg/hr (loading dose: 5 –10 mg)

*Number of doses to be given is calculated with the following formula:
24 hr
actual duration of single effective dose (hr)
Single doses should be given at calculated fixed intervals approximately 30 min before expected
recurrence of pain. Single dose should be readjusted daily. Elderly patients may be more susceptible
to opioids.
†
Dose should be adjusted according to effect and side effects.
© 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
1 BASIC SURGICAL AND PERIOPERATIVE CONSIDERATIONS 5 POSTOPERATIVE PAIN — 7

Regimens for Acute Pain Relief

It is generally agreed that at least 2 mg of epidural morphine is
needed to achieve a significant analgesic response, but the criteria
used to assess this response have varied greatly in reported stud-
ies, and no firm conclusion can be derived from them.25,27
Epidural opioids are less efficient in the earliest stages of the acute
pain state than on subsequent days; moreover, they appear to be
more successful at alleviating pain after procedures in the lower
half of the body than at alleviating upper abdominal and thoracic
pain. In general, 2 to 4 mg of morphine administered epidurally is
sufficient after minor procedures, whereas about 4 mg is needed
after vascular and gynecologic procedures and after major upper
abdominal and thoracic procedures.20,25,27 On postoperative day 1,
however, such a regimen, even when repeated as many as three
times, relieves pain completely in fewer than 50% of patients; on
subsequent days, the success rate is substantially higher. The effi-
ciency of this approach is lowest after major procedures.
There is evidence to suggest that continuous epidural adminis-
tration of low-dosage morphine (0.1 to 0.3 mg/hr) or fentanyl (10
to 20 µg/hr) may lower the risk of late respiratory depression and
may be more efficient than intermittent administration of higher
dosages of morphine.27 The continuous low-dosage approach is
therefore recommended.
regional nerve blockade. In addition, there is a great deal of exper-
imental evidence that documents the benefits of blocking noxious
impulses.28 Local anesthetic neural blockade is unique among
available analgesic techniques in that it may offer sufficient affer-
ent neural blockade, resulting in relief of pain; avoidance of seda-
tion, respiratory depression, and nausea; and, finally, efferent sym-
pathetic blockade, resulting in increased blood flow to the region
of neural blockade.28 Despite the considerable scientific data doc-
umenting these beneficial effects, the place of epidural local anes-
thesia as a method of pain relief remains somewhat controversial
in comparison with that of other analgesic techniques. Its side
effects (e.g., hypotension, urinary retention, and motor blockade)
and the need for trained staff for surveillance argue against its use;
however, these side effects can be reduced by using combination
regimens (see below).27
Mechanism of Action
Local anesthetic neural blockade is a nondepolarizing block
that reduces the permeability of cell membranes to sodium ions.29
Whether different local anesthetics have different effects on differ-
ent nerve fibers is debatable.
Choice of Drug

Side Effects For optimal management of postoperative pain, the anesthetic

agent should provide excellent analgesia of rapid onset and long
The chief side effects associated with epidural and subarach- duration without inducing motor blockade. The various local
noid opioids are respiratory depression, nausea and vomiting, pru- anesthetic agents all meet one or more of these criteria; however,
ritus, and urinary retention.25-27 The poor lipid solubility of mor- the ones that come closest to meeting all of the criteria are bupi-
phine is responsible for its protracted duration of action but also vacaine, ropivacaine, and levobupivacaine. This should not pre-
allows morphine to undergo cephalad migration in the cere- clude the use of other agents, because their efficacy has also been
brospinal fluid. This migration can cause delayed respiratory demonstrated. Ropivacaine and levobupivacaine may have a bet-
depression, with a peak incidence 3 to 10 hours after an injection. ter safety profile, but the improvement may be relevant only when
The high lipid solubility of lipophilic opioids such as fentanyl high intraoperative doses are given.29
allows them to be absorbed into lipids close to the site of admin-
istration. Consequently, the lipophilic opioids do not migrate ros- Continuous Epidural Analgesia
trally in the CSF and cannot cause delayed respiratory depression.
No regimen has been found that provides complete analgesia in
Of course, the high lipid solubility of lipophilic opioids allows
all patients all of the time, and it is unlikely that one ever will be
them to be absorbed into blood vessels, which may cause early res-
piratory depression, as is commonly seen with systemic adminis-
tration of opioids. Table 6—Regimen for Pain Relief
Naloxone reverses the depressive respiratory effects of spinal with Continuous Epidural Bupivacaine during
opioids. In an apneic patient, 0.4 mg I.V. will usually restore ven-
tilation. If a patient has a depressed respiratory rate but is still
Initial 24 Postoperative Hours
breathing, small aliquots of naloxone (0.2 to 0.4 mg) can be given
until the respiratory rate returns to normal. Interspace
Type of Concentration Volume
for Catheter
Nausea and vomiting are caused by transport of opioids to the Operation Insertion (%) (ml/hr)
vomiting center and the chemoreceptor trigger zone in the medul-
la via CSF flow or the systemic circulation. Nausea can usually be Thoracic
T4–6 0.250–0.125 5–10
treated with antiemetics or, if severe, with naloxone (in 0.2 mg procedures
increments, repeated if necessary).
Upper laparotomy T7–8 0.250–0.125 4–12
Pruritus is probably the most common side effect of the spinal
opioids. Histamine is released by certain opioids, but this mecha- Gynecologic
T10–12 0.250–0.125 4–10
nism probably plays a negligible role in the genesis of itching. laparotomy
Treatment of pruritus is similar to that of nausea.
Hip procedures L2 0.125–0.0625 4–8
The mechanism of spinal opioid–induced urinary retention in-
volves inhibition of volume-induced bladder contractions and block- Vascular T10–12 0.250–0.125 4–10
ade of the vesical reflex. Naloxone administration is the treatment of procedures
choice, though bladder catheterization is sometimes required.
Note: indications for postoperative epidural bupivacaine may be strengthened if this
method is also indicated for intraoperative analgesia. Dosage requirements may vary
EPIDURAL LOCAL ANESTHETICS AND OTHER REGIONAL and should be assessed 3 hr after the start of treatment, every 6 hr thereafter on the
BLOCKS first day, and then every 12 hr (more often if pain occurs). The duration of treatment
is 1–4 days, depending on the intensity of the pain. The concentration of bupiva-
Local anesthetics have become increasingly popular because of caine employed should be the lowest possible and should be decreased with time
postoperatively. Some patients, especially those who have undergone major upper
the growing familiarity with both epidural catheterization and abdominal operation, require 0.5% bupivacaine initially.
© 2005 WebMD, Inc. All rights reserved.
1 BASIC SURGICAL AND PERIOPERATIVE CONSIDERATIONS
Table 7—Procedures for Maintenance of
Epidural Anesthesia for Longer Than 24 Hours
1. Administer appropriate drug in appropriate dosage at selected
infusion rate as determined by physician.
2. Nurse evaluates vital signs and intake and output as required for a
postoperative patient.
3. Nurse checks infusion pump hourly to ensure that it is functioning
properly, that infusion rate is proper, and that alarm is on.
4. Nurse also assesses
• Bladder—for distention, if patient is not catheterized
• Lower extremities—for status of motor function
• CNS—for signs of toxicity or respiratory depression
• Relief of pain (drug dosage may require modification)
• Skin integrity on back (breakdown may occur if motor function
is not present)
• Tubing and dressing (disconnection of tubing or dislodgment
of catheter may occur)
5. Every 48 hr, the catheter dressing should be removed, the
catheter entrance site cleaned, and topical antibiotic applied
(much as in care of a central venous catheter).
found. As a rule, the block should be limited to the area in which
pain is felt. Care should be taken to avoid motor blockade and to
spare autonomic function to the urinary bladder, as well as to for-
mulate a regimen that requires only minimal attention from staff
members and carries no significant toxicity. Given these require-
ments, continuous infusion [see Table 6] is more effective and reli-
able than intermittent injection.27 Whether low hourly volume and
high concentration approaches are preferable to high hourly vol-
ume and low concentration approaches remains to be deter-
mined.27 The weaker solutions may produce less motor blockade
while continuing to block smaller C and A-delta pain fibers and
are recommended in lumbar epidural analgesia as a means of
reducing the risk of orthostatic hypotension and lower-extremity
motor blockade.27
Specific indications for continuous epidural analgesia that are
supported by data from controlled morbidity studies include (1) pain
relief and reduction of deep vein thrombosis, pulmonary embolism,
and hypoxemia after total hip replacement and prostatectomy; (2)
pain relief, facilitation of coughing, and reduction of chest infec-
tions after thoracic, abdominal, and orthopedic procedures; (3)
pain relief, control of hypertension, and enhancement of graft flow
after major vascular operations; and (4) pain relief and reduction
of paralytic ileus after abdominal procedures.30,31
Side Effects
The main side effects of epidural local anesthesia are hypoten-
sion caused by sympathetic blockade, vagal overactivity, and
decreased cardiac function (during a high thoracic block). Under
no circumstances should epidural local anesthetics be used before
a preexisting hypovolemic condition is treated. Hypotension may
be treated with ephedrine, 10 to 15 mg I.V., and fluids, with the
patient tilted in a head-down position. Atropine, 0.5 to 1.0 mg
I.V., may be effective during vagal overactivity.
Urinary retention occurs in 20% to 100% of patients.
Fortunately, urinary catheterization for only 24 to 48 hours in the
course of a high-dose regimen probably has no important side
effects, and many patients for whom epidural analgesia is indicat-
ed need an indwelling catheter for other reasons in any case. The
incidence of urinary retention is probably below 10% when
ACS Surgery: Principles and Practice
5 POSTOPERATIVE PAIN — 8
epidural local anesthetics are used in weak solutions.32 Motor
blockade may delay mobilization; however, its incidence can be
reduced by using the weakest concentration of local anesthetic
that is compatible with adequate sensory blockade. Cerebral and
epidural analgesia should not be employed in patients already
receiving anticoagulant therapy, but it may be started with cathe-
ter insertion before vascular or other procedures in which con-
trolled heparin therapy is used. Epidural analgesia has been used
in patients receiving thromboembolic prophylaxis with low-dose
heparin and low-molecular-weight heparin without significant
risk,27 provided that current guidelines are followed.33,34 It should
be emphasized that the heparin doses commonly employed in the
United States are higher than those recommended in Europe; the
higher doses may pose a risk when heparin prophylaxis is com-
bined with epidural analgesia.33,34 The complications associated
with the epidural catheter are minimal when proper nursing pro-
tocols are followed [see Table 7].27 The decision to employ epidur-
al local anesthetics in such patients should be made only after the
risks33,34 are carefully compared with the documented advantages
of such anesthetics.27,31 It is important that the level of insertion
into the epidural space correspond with the level of incision.
Other Nerve Blocks
The popularity of single-dose intercostal block and intrapleural
regional analgesia has decreased in comparison with that of con-
tinuous epidural treatment. Intermittent or continuous administra-
tion of local anesthetics through a catheter inserted into the paraver-
tebral space seems to be a promising approach to providing anal-
gesia after thoracic and abdominal procedures,35 but further data
are needed. Intravenous and intraperitoneal administration of local
anesthetics cannot be recommended for postoperative analgesia,
because they are not efficacious,36 except in laparoscopic cholecys-
tectomy.12,37 Intraincisional administration of bupivacaine, which has
negligible side effects and demands little or no surveillance, is rec-
ommended for patients undergoing relatively minor procedures.38
Several studies have now reported that continuous administra-
tion of local anesthetics into the wound improves postoperative
analgesia in a variety of procedures38-44; however, there is still a
need for more procedure-specific data before general recommen-
dations can be made. Continuous peripheral nerve blocks are grow-
ing in popularity, and the analgesic treatment may be continued
after discharge.15,16,45 Before general recommendations for contin-
uous peripheral blockade can be formulated, however, further
safety data are required.
More detailed information on special blocks can be found in the
anesthesiology literature. In general, despite its disadvantages,
neural blockade with local anesthetics is recommended for relief of
Table 8—Recommended Dosages of
NSAIDs or COX-2 Inhibitors for
Relief of Postoperative Pain
NSAID Dosage
Acetylsalicylic acid 500–1,000 mg q. 4–6 hr
Acetaminophen 500–1,000 mg q. 4–6 hr
Indomethacin 50–100 mg q. 6–8 hr
Ibuprofen 200–400 mg q. 4–6 hr
Ketorolac 30 mg q. 4–6 hr
Celecoxib 200–400 mg q. 12 hr
Rofecoxib 12–25 mg q. 12 hr
© 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
1 BASIC SURGICAL AND PERIOPERATIVE CONSIDERATIONS 5 POSTOPERATIVE PAIN — 9

moderate to severe postoperative pain because of the advanta- this setting,58,59 and the investigators concluded that these drugs
geous physiologic effects it exerts and the reduction in postopera- were therefore contraindicated in CABG patients. The larger
tive morbidity it brings about. question is whether these drugs should also be contraindicated for
perioperative use, or at least used with caution, in high-risk car-
CONVENTIONAL NSAIDS AND COX-2 INHIBITORS
diovascular patients who are undergoing procedures other than
NSAIDs are minor analgesics that, because of their anti-inflam- CABG. At present, the data are insufficient to allow any conclu-
matory effect, may be suitable for management of postoperative sions, but in my view, until more information is available, it may
pain associated with a significant degree of inflammation (e.g., be prudent to avoid perioperative use of COX-2 inhibitors in all
bone or soft tissue damage).46 They may, however, have central high-risk cardiovascular patients (i.e., those with uncontrolled
analgesic effects as well and thus may have analgesic efficacy after hypertension, previous myocardial infarction, heart failure, or pre-
all kinds of operations. Conventional NSAIDs inhibit both COX- vious cerebral vascular disorders). In other patients, however, peri-
1 and COX-2. Selective COX-2 inhibitors, which do not inhibit operative administration of selective COX-2 inhibitors may be jus-
COX-1, have the potential to achieve analgesic efficacy compara- tified if the advantageous effects appear to outweigh the potential
ble to that of conventional NSAIDs but with fewer side effects [see (low) risk of complications.
Table 8].47-49 Finally, the already quite low risk of NSAID-induced asthma may
Only a few of the NSAIDs may be given parenterally.The data be further reduced by the use of selective COX-2 inhibitors.48,49
now available on the use of NSAIDs for postoperative pain are Peripheral (i.e., surgical site) administration of NSAIDs may
insufficient to allow definitive recommendation of any agent or have a slight additional analgesic effect in comparison with sys-
agents over the others, and selection therefore may depend on temic administration,60 but further data on safety are required.
convenience of delivery, duration, and cost.46 It is clear, however, Acetaminophen also possesses anti-inflammatory capability,
that these agents may play a valuable role as adjuvants to other both peripherally and centrally. Its analgesic effect is somewhat
analgesics; accordingly, they have been recommended as basic (about 20% to 30%) weaker than those of conventional NSAIDs
analgesics for all operations in low-risk patients. All of the NSAIDs and COX-2 inhibitors; however, it lacks the side effects typical of
have potentially serious side effects: GI and surgical site hemor- these agents.61-63 Combining acetaminophen with NSAIDs may
rhage, renal failure, impaired bone healing and asthma. The endo- improve analgesia, especially in smaller and moderate-sized oper-
scopically verified superficial ulcer formation seen within 7 to 10
days after the initiation of NSAID therapy is not seen with selec-
tive COX-2 inhibitor treatment in volunteers. The clinical rele-
vance of these findings for perioperative treatment remains to be
established, however, given that acute severe GI side effects
(bleeding, perforation) are extremely rare in elective cases.
Because prostaglandins are important for regulation of water
and mineral homeostasis by the kidneys in the dehydrated patient,
perioperative treatment with NSAIDs, which inhibit prostaglandin
synthesis, may lead to postoperative renal failure. So far, specific
COX-2 inhibitors have not been demonstrated to be less nephro-
toxic than conventional NSAIDs.48-51 Although little systematic
evaluation has been done, extensive clinical experience with NSAIDs
suggests that the renal risk is not substantial.51 Nonetheless, con-
ventional NSAIDs and COX-2 inhibitors should be used with
caution in patients who have preexisting renal dysfunction.
Although conventional NSAIDs prolong bleeding time and
inhibit platelet aggregation, there generally does not seem to be a
clinically significant risk of increased bleeding. However, in some
procedures for which strict hemostasis is critical (e.g., tonsillectomy,
cosmetic surgery, and eye surgery), these drugs have been shown to
increase the risk of bleeding complications and should therefore be
replaced with COX-2 inhibitors, which do not inhibit platelet
aggregation.52,53 The observation that prostaglandins are involved in
bone and wound healing has given rise to concern about potential
side effects in surgical patients. Although there is experimental evi-
dence that both conventional NSAIDs and COX-2 inhibitors can
impair bone healing,54-57 the clinical data available at present are
insufficient to document wound or bone healing failure with these
drugs.This is a particularly important issue for future study, in that
many orthopedic surgeons remain reluctant to use NSAIDs.
Currently, there is widespread concern about the increased risk
of cardiovascular complications associated with long-term treat-
Figure 1 Illustrated is the procedure for performing cryoanalge-
ment with selective COX-2 inhibitors. Generally, such side effects sia in a thoracotomy. The intercostal nerve in the thoracotomy
have appeared after 1 to 2 years of treatment. In the past few years, space is isolated, together with the two intercostal nerves above the
however, two studies of patients undergoing coronary artery space and the two below it, and the cryoprobe is applied to the
bypass grafting (CABG) found that the risk of cardiovascular nerves for 45 seconds. The probe is then defrosted and reapplied to
complications was increased significantly (two- to threefold) in the nerves for 45 seconds.The analgesia obtained lasts about 30 days.
© 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
1 BASIC SURGICAL AND PERIOPERATIVE CONSIDERATIONS 5 POSTOPERATIVE PAIN — 10

ations61-62; accordingly, this agent is recommended as a basic com-

ponent of multimodal analgesia in all operations.
Table 9—Prescription Guidelines for Intravenous
Despite the gaps in our current understanding of the workings and Patient-Controlled Analgesia
differential effects of NSAIDs and COX-2 inhibitors, what is known
is sufficiently encouraging to suggest that they should be recommend- Drug (Concentration) Demand Dose Lockout Interval (min)
ed for baseline analgesic treatment after most operative procedures,
Morphine
with the exceptions already mentioned (see above). This recom- 0.5–3.0 mg 5–12
(1 mg/ml)
mendation is based not only on their analgesic efficacy but also on their
opioid-sparing effect, which may enhance recovery (see below). Meperidine
5–30 mg 5–12
(10 mg/ml)
Glucocorticoids are powerful anti-inflammatory agents and
have proven analgesic value in less extensive procedures,64 espe- Fentanyl
10–20 µg 5–10
(10 µg/ml)
cially dental, laparoscopic, and arthroscopic operations. In addi-
tion, they have profound antiemetic effects. Concerns about pos- Hydromorphone
0.1–0.5 mg 5–10
sible side effects in the setting of perioperative administration have (0.2 mg/ml)
not been borne out by the results of randomized studies.64 Oxymorphone
0.2–0.4 mg 8–10
(0.25 mg/ml)
OTHER ANALGESICS
Methadone
Tramadol is a weak analgesic that has several relatively minor 0.5–2.5 mg 8–20
(1 mg/ml)
side effects (e.g., dizziness, nausea, and vomiting).65 It can be com-
Nalbuphine
bined with acetaminophen to yield analgesic activity comparable 1–5 mg 5–10
(1 mg/ml)
to that of NSAIDs.66
Several systematic reviews have suggested that some analgesic
and perioperative opioid-sparing effects can be achieved by adding the widespread patient satisfaction with patient-controlled analge-
an N-methyl-D-aspartate receptor antagonist (e.g., ketamine),67-69 sia (PCA).75,76 It must be emphasized, however, that the effect of
gabapentin, or pregabalin70 [see Combination Regimens, below]. PCA on movement-associated pain is limited in comparison with
that of epidural local anesthesia.14
CRYOANALGESIA

Cryoanalgesia is the application of low temperatures (–20º to Mechanisms of Action

–29º C) to peripheral nerves with the goal of producing axonal
degeneration and thus analgesia [see Figure 1]. Axonal regeneration
takes place at a rate of 1 to 3 mm/day, which means that analgesia
after intercostal blocks lasts about 30 days. Cryoanalgesia has no
cardiac, respiratory, or cerebral side effects, and local side effects
(e.g., neuroma formation) are extremely rare. In this context, it
should be emphasized that postthoracotomy patients are at sub-
stantial risk (~30%) for chronic neuropathic pain without the use of
cryoanalgesia71; however, this technique can be used only on senso-
ry nerves or on nerves supplying muscles of no clinical importance.
At present, no information is available on the use of cryoanal-
gesia in operative procedures other than herniotomy and thoracot-
omy.72 Cryoanalgesia is not efficacious after herniotomy.73 The data
on postthoracotomy cryoanalgesia, however, suggest improved
pain alleviation and a concomitant reduction in the need for nar-
cotics, which, in conjunction with the simplicity and low cost of
the modality and the absence of side effects, present a strong argu-
ment for more extensive use of cryoanalgesia.
TRANSCUTANEOUS ELECTRICAL NERVE STIMULATION
Transcutaneous electrical nerve stimulation (TENS) is the
application of a mild electrical current through the skin surface
to a specific area, such as a surgical wound, to achieve pain relief;
the exact mechanism whereby it achieves this effect is yet to be
explained. Many TENS devices are available for clinical use, but
the specific values and the proper uses of the various stimulation
frequencies, waveforms, and current intensities have not been
determined. Unfortunately, the effect of TENS on acute pain is
too small to warrant a recommendation for routine use.74
PATIENT-CONTROLLED ANALGESIA
Patient-controlled administration of opioids has experienced a
dramatic increase in use. This increase may be attributed to (1)
awareness of the inadequacy of traditional I.M. opioid regimens,
(2) the development of effective and safe biotechnology, and (3)
Traditional I.M. dosing of opioids does not result in consistent
blood levels,75,76 because opioids are absorbed at a variable rate
from the vascular bed of muscle. Moreover, administration of tra-
ditional I.M. regimens results in opioid concentrations that exceed
the concentrations required to produce analgesia only about 30%
of the time during any 4-hour dosing interval. PCA avoids these
pitfalls by allowing repeated dosing on demand. PCA yields more
constant and consistent plasma opioid levels and therefore pro-
vides better analgesia.75,76
Modes of Administration and Dosing Parameters
There are several modes by which opioids can be administered
under patient control. Intermittent delivery of a fixed dose is known
as demand dosing. Background infusions have been used to sup-
plement patient-administered doses, but this practice increases the
risk of respiratory depression and should therefore be avoided.75,76
There are several basic prescription parameters for PCA: load-
ing dose, demand dose, lockout interval, and 4-hour limits [see
Table 9].75,76 When PCA is used for postoperative care, it is usual-
ly initiated in the recovery room.The patient is made comfortable
by administering as much opioid as is needed (i.e., a loading
dose). When the patient is sufficiently recovered from the anes-
thetic, he or she may begin to use the infuser.
Side Effects
Minor side effects associated with PCA include nausea, vomiting,
sweating, and pruritus. Clinically significant respiratory depression with
PCA is rare.There is no evidence to suggest that PCA is associated with
a higher incidence of side effects than are other routes of systemic
opioid administration.75,76 Side effects are the result of the pharma-
cologic properties of opioids, not the method of administration.75,76
COMBINATION REGIMENS
Because no single pain treatment modality is optimal, combi-
nation regimens (e.g., balanced analgesia or multimodal treatment)
© 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
1 BASIC SURGICAL AND PERIOPERATIVE CONSIDERATIONS 5 POSTOPERATIVE PAIN — 11

offer major advantages over single-modality regimens, whether by
maintaining or improving analgesia, by reducing side effects, or by
doing both.77,78 Combinations of epidural local anesthetics and
morphine,14,27 of NSAIDs and opioids,46,77,78 of NSAIDs and
acetaminophen,61,62 of acetaminophen and opioids,63 of aceta-
minophen and tramadol,66 and of a selective COX-2 inhibitor and
gabapentin79 have been reported to have additive effects. At pres-
ent, information on other combinations (involving ketamine,
clonidine, glucocorticoids, and other agents) is too sparse to allow
firm recommendations; however, multimodal analgesia is
undoubtedly promising, and multidrug combinations should cer-
tainly be explored further.
Perception of Pain
The potential of combination regimens is especially intriguing
with respect to the concept of perioperative opioid-sparing anal-
gesia.The use of one or several nonopioid analgesics in such regi-
mens may enhance recovery, in that the concomitant reduction in
the opioid dosage will lead to decreased nausea, vomiting, and
sedation.80-84 Both the adverse events associated with postopera-
tive opioid analgesia and the relatively high costs of such analgesia
argue for an opioid-sparing approach.85,86 Another argument that
has been advanced is that the introduction of the JCAHO pain ini-
tiative may precipitate increased use of opioids (and thereby an
increased risk of side effects), though it is not certain that this will
be the case.87,88

Figure 2 Shown are the major neural pathways involved in

nociception. Nociceptive input is transmitted from the
periphery to the dorsal horn via A-delta and C fibers (for
somatic pain) or via afferent sympathetic pathways (for vis-
ceral pain). It is then modulated by control systems in the
dorsal horn and sent via the spinothalamic tracts and spin-
oreticular systems to the hypothalamus, to the brain stem
and reticular formation, and eventually to the cerebral cor-
tex. Ascending transmission of nociceptive input is also mod-
ulated by descending inhibitory pathways originating in the
brain and terminating in the dorsal horn. Nociception may
be enhanced by reflex responses that affect the environment
of the nociceptors, such as smooth muscle spasm.

Trauma
Capillary

To the Limbic System Descending Inhibitory Pathway

Neurotransmitters at
Dorsal Horn Level:
Norepinephrine Release of:
Serotonin Substance P
Enkephalins Histamine
Serotonin
Primary Afferent Bradykinin
Neurotransmitter Prostaglandins
Candidates
Substance P
Spinothalamic Tract L-Glutamate
GABA
VIP Release of:
CCK-8 Norepinephrine
Sensory Nerve
Somatostatin

Muscle

Motor of Other Efferent Nerve

Segmental Reflexes:
Increased Skeletal Muscle Tension
Decreased Chest Compliance
More Nociceptive Input
Increased Sympathetic Tone
Decreased Gastric Mobility
IIeus, Nausea, Vomiting
© 2005 WebMD, Inc. All rights reserved.
1 BASIC SURGICAL AND PERIOPERATIVE CONSIDERATIONS
Discussion
Physiologic Mechanisms of Acute Pain
The basic mechanisms of acute pain are (1) afferent transmis-
sion of nociceptive stimuli through the peripheral nervous system
after tissue damage, (2) modulation of these injury signals by con-
trol systems in the dorsal horn, and (3) modulation of the ascend-
ing transmission of pain stimuli by a descending control system
originating in the brain [see Figure 2].89-92
PERIPHERAL PAIN RECEPTORS AND NEURAL
TRANSMISSION TO SPINAL CORD
Peripheral pain receptors (nociceptors) can be identified by
function but cannot be distinguished anatomically. The respon-
siveness of peripheral pain receptors may be enhanced by endoge-
nous analgesic substances (e.g., prostaglandins, serotonin,
bradykinin, nerve growth factor, and histamine), as well as by
increased efferent sympathetic activity.89 Antidromic release of
substance P may amplify the inflammatory response and thereby
increase pain transmission.The peripheral mechanisms of visceral
pain still are not well understood90 —for example, no one has yet
explained why cutting or burning may provoke pain in the skin but
not provoke pain in visceral organs. Peripheral opioid receptors
have been demonstrated to appear in inflammation on the periph-
eral nerve terminals, and clinical studies have demonstrated that
there are analgesic effects from peripheral opioid administration
during arthroscopic knee surgery.93
Somatic nociceptive input is transmitted to the CNS through
A-delta and C fibers, which are small in diameter and either
unmyelinated or thinly myelinated. Visceral pain is transmitted
through afferent sympathetic pathways; the evidence that afferent
parasympathetic pathways play a role in visceral nociception is
inconclusive.90
DORSAL HORN CONTROL SYSTEMS AND MODULATION
OF INCOMING SIGNALS
All incoming nociceptive traffic synapses in the gray matter of
the dorsal horn (Rexed’s laminae I to IV). Several substances may
be involved in primary afferent transmission of nociceptive stimuli
in the dorsal horn: substance P, enkephalins, somatostatin, neu-
rotensin, γ-aminobutyric acid (GABA), glutamic acid, angiotensin
II, vasoactive intestinal polypeptide (VIP), and cholecystokinin
octapeptide (CCK-8).91 From the dorsal horn, nociceptive infor-
mation is transmitted through the spinothalamic tracts to the
hypothalamus, through spinoreticular systems to the brain stem
and reticular formation, and finally to the cerebral cortex.
DESCENDING PAIN CONTROL SYSTEM
A descending control system for sensory input originates in the
brain stem and reticular formation and in certain higher brain
areas. The main neurotransmitters in this system are norepineph-
rine, serotonin, and enkephalins. Epidural-intrathecal administra-
tion of alpha-adrenergic agonists (e.g., clonidine) may therefore
provide pain relief.91
SPINAL REFLEXES
Nociception may be enhanced by spinal reflexes that affect the
environment of the nociceptive nerve endings. Thus, tissue dam-
age may provoke an afferent reflex that causes muscle spasm in the
vicinity of the injury, thereby increasing nociception. Similarly,
sympathetic reflexes may cause decreased microcirculation in
ACS Surgery: Principles and Practice
5 POSTOPERATIVE PAIN — 12
injury tissue, thereby generating smooth muscle spasm, which am-
plifies the sensation.
POSTINJURY CHANGES IN PERIPHERAL AND
CENTRAL NERVOUS SYSTEMS
After an injury, the afferent nociceptive pathways undergo phys-
iologic, anatomic, and chemical changes.91,92 These changes
include increased sensitivity on the part of peripheral nociceptors,
as well as the growth of sprouts from damaged nerve fibers that
become sensitive to mechanical and alpha-adrenergic stimuli and
eventually begin to fire spontaneously. Moreover, excitability may
be increased in the spinal cord, which leads to expansion of recep-
tive fields in dorsal horn cells. Such changes may lower pain
thresholds, may increase afferent barrage in the late postinjury
state, and, if normal regression does not occur during convales-
cence, may contribute to a chronic pain state.91
Neural stimuli have generally been considered to be the main
factor responsible for initiation of spinal neuroplasticity; however,
it now appears that such neuroplasticity may also be mediated by
cytokines released as a consequence of COX-2 induction.92
Improved understanding of the mechanisms of pain may serve as
a rational basis for future drug development and may help direct
therapy away from symptom control and toward mechanism-spe-
cific treatment.94
In experimental studies, acute pain behavior or hyperexcitabili-
ty of dorsal horn neurons may be eliminated or reduced if the
afferent barrage is prevented from reaching the CNS. Preinjury
neural blockade with local anesthetics or opioids can suppress
excitability of the CNS; this is called preemptive analgesia.
Because similar antinociceptive procedures were less effective in
experimental studies when applied after injury, timing of analgesia
seems to be important in the treatment of postoperative pain;
however, a critical analysis of controlled clinical studies that com-
pared the efficacy of analgesic regimens administered preopera-
tively with the efficacy of the same regimens administered postop-
eratively concluded that preemptive analgesia does not always pro-
vide a clinically significant increase in pain relief.95,96 Nonetheless,
it is important that pain treatment be initiated early to ensure that
patients do not wake up with high-intensity pain. As long as the
afferent input from the surgical wound continues, continuous
treatment with multimodal or balanced analgesia may be the most
effective method of treating postoperative pain.95,97
Effects of Pain Relief
METABOLIC RESPONSE TO OPERATION
It still is not generally appreciated that acute pain in the post-
operative period or after hospitalization for accidental injury not
only serves no useful function but also may actually exert harmful
physiologic and psychological effects.Therefore, except in the ini-
tial stage in acutely injured hypovolemic patients for whom
increased sympathetic activity may provide cardiovascular sup-
port, the pain-induced reflex responses that may adversely affect
respiratory function, increase cardiac demands, decrease intestinal
motility, and initiate skeletal muscle spasm (thereby impairing
mobilization) should be counteracted by all available means.
The traditional view of the physiologic role of the stress response
to surgical injury is that it is a homeostatic defense mechanism that
helps the body heal tissue and adapt to injury. However, the neces-
© 2005 WebMD, Inc. All rights reserved.
1 BASIC SURGICAL AND PERIOPERATIVE CONSIDERATIONS
sity for the stress response in modern anesthesiology and surgery
has been questioned.28 Thus, concern about the detrimental effects
of operative procedures (e.g., myocardial infarction, pulmonary
complications, and thromboembolism) that cannot be attributed
solely to imperfections in surgical technique has led to the hypoth-
esis that the unsupported continuous injury response may instead
be a maladaptive response that erodes body mass and physiologic
reserve.28,98 Because neural stimuli play an important role in releas-
ing the stress response to surgical injury, pain relief may modify this
response, but this modulation is dependent on the mechanism of
action of the pain treatment modality employed.28
Alleviation of pain through antagonism of peripheral pain medi-
ators (i.e., through use of NSAIDs) has no important modifying
effect on the response to operation.22,30 The effects of blockade of
afferent and efferent transmission of pain stimuli by means of
regional anesthesia have been studied in detail.22,31 Spinal or
epidural analgesia with local anesthetics prevents the greater part
of the classic endocrine metabolic response to operative proce-
dures in the lower region of the body (e.g., gynecologic and uro-
logic procedures and orthopedic procedures in the lower limbs)
and improves protein economy; however, this effect is consider-
ably weaker in major abdominal and thoracic procedures, proba-
bly because of insufficient afferent neural blockade. The modify-
ing effect of epidural analgesia on the stress response is most pro-
nounced if the neural blockade takes effect before the surgical
insult.The optimal duration of neural blockade for attenuating the
hypermetabolic response has not been established, but it should
include at least the initial 24 to 48 hours.22,31
Alleviation of postoperative pain through administration of
epidural-intrathecal opioids has a smaller modifying effect on the
surgical stress response, in comparison with the degree of pain
relief it provides22,31; furthermore, it does not provide efferent sym-
pathetic blockade. Systemic administration of opioids, either ac-
cording to a fixed administration regimen or according to a demand-
based regimen, has no important modifying effect on the stress
response.22 The effects of pain relief by acetaminophen, tramadol,
cryoanalgesia, or TENS on the stress response have not been estab-
lished but probably are of no clinical significance. Further studies
aimed at defining the effects of multimodal analgesia on the sur-
gical stress response are required.
POSTOPERATIVE MORBIDITY
The effects of nociceptive blockade and pain relief on postop-
erative morbidity remain to be defined, except with respect to
intraoperative spinal or epidural local anesthetics in lower-body
procedures, about which the following four conclusions can be
made.22,99 First, intraoperative blood loss is reduced by about
30%. Second, thromboembolic and pulmonary complications are
reduced by about 30% to 40%. Third, when epidural local anes-
thetics are continuously administered (with or without small doses
of opioids) to patients undergoing abdominal or thoracic proce-
dures, pulmonary infectious complications appear to be reduced
by about 40%.30 Fourth, the duration of postoperative ileus is
reduced14,31; this effect may be of major significance, in that reduc-
tion of ileus allows earlier oral nutrition,31 which has been demon-
strated to improve outcome.
The impact of continuous epidural analgesia on postoperative
outcome after major operations remains the subject of some debate.
Three large randomized trials from 2001 and 2002 found no pos-
itive effects except for improved pulmonary outcome.100-102 One
explanation for these negative findings may be the use of a pre-
dominantly opioid-based epidural analgesic regimen, which would
hinder the normal physiologic responses supporting recovery to a
ACS Surgery: Principles and Practice
5 POSTOPERATIVE PAIN — 13
greater extent than a local anesthetic regimen would.22 Another
explanation may be inadequate study design in some cases: most
studies to date have focused on the effects of a single factor (i.e.,
epidural analgesia) on overall postoperative morbidity, which is
probably too simplistic an approach, given that overall postopera-
tive outcome is known to be determined by multiple factors.103,104
Besides postoperative pain relief, reinforced psychological prepa-
ration of the patient, reduction of stress by performing neural
blockade or opting for minimal invasive procedures, and enforce-
ment of early oral postoperative feeding and mobilization may all
play a significant role in determining outcome.103,104 Prevention of
intraoperative hypothermia, avoidance of fluid overloading, and
avoidance of hypoxemia may be important as well.103,104
Therefore, although adequate pain relief is obviously a prereq-
uisite for good outcome, the best results are likely to be achieved
by combining analgesia with all the aforementioned factors in a
multimodal rehabilitation effort.103,104 Observations from patients
undergoing a variety of surgical procedures suggest that such a
multimodal approach may lead to significant reductions in hospi-
tal stay, morbidity, and convalescence.103,104 Admittedly, these pre-
liminary observations require confirmation by randomized or
multicenter trials. The role of the acute pain service105 and the
effect of establishing a postoperative rehabilitation unit should be
assessed as well.
TOLERANCE, PHYSICAL DEPENDENCE, AND ADDICTION
Continued exposure of an opioid receptor to high concentra-
tions of opioid will cause tolerance. Tolerance is the progressive
decline in an opioid’s potency with continuous use, so that higher
and higher concentrations of the drug are required to cause the
same analgesic effect. Physical dependence refers to the produc-
tion of an abstinence syndrome when an opioid is withdrawn. It is
defined by the World Health Organization as follows106:
A state, psychic or sometimes also physical, resulting from interactions
between a living organism and a drug, characterized by behavioural
and other responses that always include a compulsion to take the drug
on a continuous or periodic basis in order to experience its psychic
effects, and sometimes to avoid discomfort from its absence.
This definition is very close to the popular conception of addic-
tion. It is important, however, to distinguish addiction (implying
compulsive behavior and psychological dependence) from toler-
ance (a pharmacologic property) and from physical dependence
(a characteristic physiologic effect of a group of drugs). Physical
dependence does not imply addiction. Moreover, tolerance can
occur without physical dependence; the converse does not appear
to be true.
The possibility that the medical administration of opioids could
result in a patient’s becoming addicted has generated much debate
about the use of opioids. In a prospective study of 12,000 hospi-
talized patients receiving at least one strong opioid for a protract-
ed period, there were only four reasonably well documented cases
of subsequent addiction, and in none of these was there a history
of previous substance abuse.107 Thus, the iatrogenic production of
opioid addiction may be very rare.
CONCLUSION
The choice of therapeutic intervention for acute postoperative
pain is determined largely by the nature of the patient’s problem,
the resources available, the efficacy of the various treatment tech-
niques, the risks attendant on the procedures under consideration,
and the cost to the patient.108 Whereas trauma has been the sub-
ject of intensive research, the mechanisms of the pain associated
© 2005 WebMD, Inc. All rights reserved.
1 BASIC SURGICAL AND PERIOPERATIVE CONSIDERATIONS
with trauma and surgical injury and the optimal methods of reliev-
ing such pain have received comparatively little attention from sur-
geons. It is to be hoped that our growing understanding of basic
pain mechanisms and appropriate therapy, combined with the
promising data supporting the idea that adequate inhibition of
surgically induced nociceptive stimuli may reduce postoperative
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